Biemamides and related scaffolds as inhibitors of transforming growth factor-beta signaling

Abstract

The present technology provides an isolated compound of Formula I, compositions including such compounds, methods of inhibiting TGF-β signaling and/or TGF-β induced epithelial mesenchymal transitions (EMT), and treating certain cancers involving TGF-β signaling and/or EMT.

What is claimed is: 
     
       1. A method of treatment comprising administering to a mammal suffering from a disease or disorder mediated by TGF-β signaling, an effective amount of a compound of Formula I, a stereoisomer, tautomer, and/or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the effective amount of the compound of Formula I, stereoisomer, tautomer, and/or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the compound of Formula I has the structure 
       
         
           
           
               
               
           
         
       
       and wherein:
 R 1  is a C 12 -C 18  alkyl or alkenyl; 
 R 2  is a C 1 -C 6  alkyl; and 
 n is 1, 2, 3, 4, 5, or 6. 
 
     
     
       2. The method of  claim 1 , wherein the isolated compound is a compound of Formulae IIA, IIB, IIC, IID, or IIE, 
       
         
           
           
               
               
           
         
       
       tautomers thereof and/or pharmaceutically acceptable salts thereof. 
     
     
       3. The method of  claim 1 , wherein the mammal is human. 
     
     
       4. The method of  claim 1 , wherein the disease or disorder is liver fibrosis, lung fibrosis, kidney fibrosis, skin fibrosis, or myelofibrosis. 
     
     
       5. The method of  claim 1 , wherein the disease or disorder is selected from the group consisting of hepatocellular carcinoma or non-small cell lung cancer. 
     
     
       6. A method of inhibiting TGF-β signaling comprising contacting a TGF-β signaling system with an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
         a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1  is a C12-Cis alkyl or alkenyl; 
         R 2  is a C 1 -C 6  alkyl; and 
         n is 1, 2, 3, 4, 5, or 6; 
         or a pharmaceutical composition comprising the effective amount of the compound of Formula I, stereoisomer, tautomer, and/or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the effective amount inhibits TGF-β signaling. 
       
     
     
       7. The method of  claim 6 , wherein the compound inhibits TGF-β signaling at concentrations of about 0.5 nM to about 100 μM. 
     
     
       8. The method of  claim 6 , wherein the effective amount inhibits TGF-β induced epithelial mesenchymal transitions (EMT). 
     
     
       9. The method of  claim 6 , wherein the compound of Formula I is a compound of Formulae IIA, IIB, IIC, IID, or IIE, 
       
         
           
           
               
               
           
         
       
       tautomers thereof and/or pharmaceutically acceptable salts thereof.